Dust exposure, pneumoconiosis, and mortality of coalminers.
General mortality in approximately 25 000 British coalminers over 22 year periods ending in 1980 was 13% lower on average than in English and Welsh men in the same regions of Britain. There were significant within region variations between collieries, and standardised mortality ratios increased during the later years of the follow up, approaching or slightly exceeding 100 in most of the 20 coalmines studied. Age specific comparisons of 22 year survival rates were made in subgroups. Relative risks of death from all non-violent causes for men with the earliest stage of progressive massive fibrosis (PMF category A), compared with risks in miners with no pneumoconiosis (category O), ranged from 1.2 in those aged 55-64 initially to 3.5 for those aged 25-34. Mortality in miners with higher categories of PMF (B or C) was even more severe. Survival rates in men with category 1 simple pneumoconiosis were about 2% to 3% lower than in miners with radiographs classified as category O, but there was no consistent evidence of an increase in mortality with increasing category of simple pneumoconiosis. Mortality from all non-violent causes increased systematically with increases in estimates of exposure to dust before the start of the follow up. That gradient was attributable primarily to deaths certified as due to pneumoconiosis and those recorded as due to bronchitis and emphysema (p less than 0.001). There was some evidence of a dust related increase in deaths from cancers of the digestive system (p approximately equal to 0.05), but none of an association between exposure to coalmine dust and lung cancer. Lung cancer mortality, assessed over 17 year periods, was about 5.5 times higher in smokers than in life long non-smokers. Smokers with no pneumoconiosis had slightly higher lung cancer death rates than smokers with pneumoconiosis. We conclude that miners exposed to excessive amounts of respirable coalmine dust are at increased risk of premature death, either from progressive massive fibrosis or from chronic bronchitis or emphysema.


MicroRNA-mediated non-cell-autonomous regulation of cortical radial glial transformation revealed by a Dicer1 knockout mouse model.
Radial glia (RG), as neurogenic progenitors and neuronal migration scaffolds, play critical roles during cortical neurogenesis. RG transformation into astrocytes, marking the transition from developmental to physiological function of these cells, is an important step during cortical development. In this study, we aim to determine the roles of microRNAs (miRNAs) during this biological process. In a conditional Dicer1-null mouse where Dicer1 is deleted in both RG and their neuronal progeny, we observe delayed RG transformation as revealed by the persistence of their radial processes, and reduced number and complexity of translocated RG cell bodies in the postnatal cerebral cortex. Downregulation of Notch1 signaling is crucial to RG transformation, and consistently we find that Notch1 signaling is enhanced in the Dicer1-null cerebral cortex. In addition, we show that, among the Notch1 ligands, Jagged2 (Jag2) is preferentially upregulated in the postnatal Dicer1-null cerebral cortex as well as primary embryonic cortical cultures with instant Dicer1 deletion. Functionally, Dicer1-deleted postnatal cerebellar cells with elevated Jag2 expression stimulate a stronger Notch1 signaling in a RG clone L2.3 when co-cultured than control cells. Therefore, we unravel a novel non-cell-autonomous mechanism that regulates RG transformation by modulating Notch1 signaling via miRNA-mediated suppression of the Nocth1 ligand Jag2. Furthermore, we validate Jag2 as a miR-124 target gene and demonstrate in vitro that Jag2 expression is highly sensitive to Dicer1 deletion. Finally, we propose a new concept of MiRNA-Sensitive target genes, identification of which may unravel a unique mode of miRNA-mediated gene expression regulation.


Rapid immunochromatographic tests for the diagnosis of chronic Chagas disease in at-risk populations: A systematic review and meta-analysis.
Despite of a high disease burden, mainly in Latin America, Chagas disease (CD) is underdiagnosed and undertreated. Rapid diagnostic tests (RDTs) might improve the access to diagnosis. The aim of this study is to review the accuracy of commercially available RDTs used in field conditions for the diagnosis of chronic CD in populations at risk, in endemic and non-endemic countries. We undertook a comprehensive search of the following databases: PubMed, SCOPUS, LILACS (last up-date on the 01st July, 2017), without language or date limits. Non-electronic sources have been also searched. This review included clinical studies with cohort recruitment of individuals at risk of T. cruzi exposure, without age limits; adequate reference standards for the diagnosis of CD. We excluded case-control studies and those testing RDTs during acute CD. Data on test accuracies were pooled through a bivariate random-effects model. Only one index test was evaluated separately. Geographical area, commercial brand, disease prevalence, study size, and risk of bias were explored as possible source of heterogeneity. Values of sensitivity and specificity were computed to obtain summary positive/negative likelihood ratios, and summary diagnostic odds ratio. Ten studies were included on six different immunochromatographic RDTs. The pooled sensitivity and specificity of the RDTs resulted 96.6% (95% CI 91.3-98.7%) and 99.3% (95% CI 98.4-99.7%), respectively. Test accuracy was particularly good in endemic areas (98.07%/99.03% of sensitivity/specificity, respectively). One test (Stat-Pak) showed an overall sensitivity of 97% (95% CI 87.6-99.3) and specificity of 99.4% (95% CI 98.6-99.8). RDTs demonstrated to be sufficiently accurate to recommend their use for screening in endemic areas, even as stand-alone tests. This approach might increase the accessibility to the diagnosis. However, an additional confirmatory test in case of positive result remains a prudent approach.


Arabidopsis UVH6, a homolog of human XPD and yeast RAD3 DNA repair genes, functions in DNA repair and is essential for plant growth.
To evaluate the genetic control of stress responses in Arabidopsis, we have analyzed a mutant (uvh6-1) that exhibits increased sensitivity to UV light, a yellow-green leaf coloration, and mild growth defects. We have mapped the uvh6-1 locus to chromosome I and have identified a candidate gene, AtXPD, within the corresponding region. This gene shows sequence similarity to the human (Homo sapiens) XPD and yeast (Saccharomyces cerevisiae) RAD3 genes required for nucleotide excision repair. We propose that UVH6 is equivalent to AtXPD because uvh6-1 mutants carry a mutation in a conserved residue of AtXPD and because transformation of uvh6-1 mutants with wild-type AtXPD DNA suppresses both UV sensitivity and other defective phenotypes. Furthermore, the UVH6/AtXPD protein appears to play a role in repair of UV photoproducts because the uvh6-1 mutant exhibits a moderate defect in the excision of UV photoproducts. This defect is also suppressed by transformation with UVH6/AtXPD DNA. We have further identified a T-DNA insertion in the UVH6/AtXPD gene (uvh6-2). Plants carrying homozygous insertions were not detected in analyses of progeny from plants heterozygous for the insertion. Thus, homozygous insertions appear to be lethal. We conclude that the UVH6/AtXPD gene is required for UV resistance and is an essential gene in Arabidopsis.


Hierarchical classification-based pan-cancer methylation analysis to classify primary cancer.
Hierarchical classification offers a more specific categorization of data and breaks down large classification problems into subproblems, providing improved prediction accuracy and predictive power for undefined categories, while also mitigating the impact of poor-quality data. Despite these advantages, its application in predicting primary cancer is rare. To leverage the similarity of cancers and the specificity of methylation patterns among them, we developed the Cancer Hierarchy Classification Tool (CHCT) using the idea of hierarchical classification, with methylation data from 30 cancer types and 8239 methylome samples downloaded from publicly available databases (The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO)). We used unsupervised clustering to divide the classification subproblems and screened differentially methylated sites using Analysis of variance (ANOVA) test, Tukey-kramer test, and Boruta algorithms to construct models for each classifier module. After validation, CHCT accurately classified 1568 out of 1660 cases in the test set, with an average accuracy of 94.46%. We further curated an independent validation cohort of 677 cancer samples from GEO and assigned a diagnosis using CHCT, which showed high diagnostic potential with generally high accuracies (an average accuracy of 91.40%). Moreover, CHCT demonstrates predictive capability for additional cancer types beyond its original classifier scope as demonstrated in the medulloblastoma and pituitary tumor datasets. In summary, CHCT can hierarchically classify primary cancer by methylation profile, by splitting a large-scale classification of 30 cancer types into ten smaller classification problems. These results indicate that cancer hierarchical classification has the potential to be an accurate and robust cancer classification method.


Augmentation of exercise ventilation by medroxyprogesterone acetate.
The influence of medroxyprogesterone acetate (MPA) on exercise performance was studied in a double-blind cross-over trial using six normal males to compare the exercise performance changes to those observed in a previous study of exercise responses of female subjects during the follicular and luteal phase of the menstrual cycle. A maximal progressive work exercise test on a cycle ergometer was performed after 2 weeks of placebo or MPA administration. Although five of six subjects spontaneously complained of increased exertional dyspnoea on MPA, no significant decreases were documented in maximal exercise time or in maximal oxygen consumption. A mean increase in exercise ventilation of 19% at low levels of exertion and 26% at high levels of exertion was documented, but no subject demonstrated evidence of ventilatory limitation. The increases in exercise ventilation observed in these male subjects after MPA administration were larger than those observed in the previous study comparing exercise ventilatory responses during follicular and luteal phases of the menstrual cycle. It seems possible that some other exercise-related modulator of the ventilatory response to exercise under the influence of progesterone is present in either male subjects receiving MPA or women with normal hormonal cycles.


Computer-aided prediction of gangrenous and perforating appendicitis.
The clinical details of 100 patients with proved acute appendicitis were compared with those of 100 patients with perforating or gangrenous appendicitis. Twenty features were found to be significantly different between the two groups. This information was incorporated into a computer data base and used in the differential diagnosis of abdominal pain. A program written to predict the probability that gangrene or perforation was present in patients with appendicitis gave a diagnostic accuracy over 91%. A clinical scoring index, which accurately predicted the state of the appendix in 88% of patients, was constructed from the significant differences between the two groups. When clinical scoring or computer analysis predicts a high probability of perforation or gangrene in patients with appendicitis, surgery should be performed without delay.


Coevolution in management fashion: an agent-based model of consultant-driven innovation.
The rise of management consultancy has been accompanied by increasingly marked faddish cycles in management techniques, but the mechanisms that underlie this relationship are not well understood. The authors develop a simple agent-based framework that models innovation adoption and abandonment on both the supply and demand sides. In opposition to conceptions of consultants as rhetorical wizards who engineer waves of management fashion, firms and consultants are treated as boundedly rational actors who chase the secrets of success by mimicking their highest-performing peers. Computational experiments demonstrate that consultant-driven versions of this dynamic in which the outcomes of firms are strongly conditioned by their choice of consultant are robustly faddish. The invasion of boom markets by low-quality consultants undercuts popular innovations while simultaneously restarting the fashion cycle by prompting the flight of high-quality consultants into less densely occupied niches. Computational experiments also indicate conditions involving consultant mobility, aspiration levels, mimic probabilities, and client-provider matching that attenuate faddishness.


Which Micropollutants in Water Environments Deserve More Attention Globally?
Increasing chemical pollution of aquatic environments is a growing concern with global relevance. A large number of organic chemicals are termed as "micropollutants" due to their low concentrations, and long-term exposure to micropollutants may pose considerable risks to aquatic organisms and human health. In recent decades, numerous treatment methods and technologies have been proposed to remove micropollutants in water, and typically several micropollutants were chosen as target pollutants to evaluate removal efficiencies. However, it is often unclear whether their toxicity and occurrence levels and frequencies enable them to contribute significantly to the overall chemical pollution in global aquatic environments. This review intends to answer an important lingering question: Which micropollutants or class of micropollutants deserve more attention globally and should be removed with higher priority? Different risk-based prioritization approaches were used to address this question. The risk quotient (RQ) method was found to be a feasible approach to prioritize micropollutants in a large scale due to its relatively simple assessment procedure and extensive use. A total of 83 prioritization case studies using the RQ method in the past decade were compiled, and 473 compounds that were selected by screening 3466 compounds of three broad classes (pharmaceuticals and personal care products (PPCPs), pesticides, and industrial chemicals) were found to have risks (RQ > 0.01). To determine the micropollutants of global importance, we propose an overall risk surrogate, that is, the weighted average risk quotient (WARQ). The WARQ integrates the risk intensity and frequency of micropollutants in global aquatic environments to achieve a more comprehensive priority determination. Through metadata analysis, we recommend a ranked list of 53 micropollutants, including 36 PPCPs (e.g., sulfamethoxazole and ibuprofen), seven pesticides (e.g., heptachlor and diazinon), and 10 industrial chemicals (e.g., perfluorooctanesulfonic acid and 4-nonylphenol) for risk management and remediation efforts. One caveat is that the ranked list of global importance does not consider transformation products of micropollutants (including disinfection byproducts) and new forms of pollutants (including antibiotic resistance genes and microplastics), and this list of global importance may not be directly applicable to a specific region or country. Also, it needs mentioning that there might be no best answer toward this question, and hopefully this review can act as a small step toward a better answer.


Defective liver formation and liver cell apoptosis in mice lacking the stress signaling kinase SEK1/MKK4.
The stress signaling kinase SEK1/MKK4 is a direct activator of stress-activated protein kinases (SAPKs; also called Jun-N-terminal kinases, JNKs) in response to a variety of cellular stresses, such as changes in osmolarity, metabolic poisons, DNA damage, heat shock or inflammatory cytokines. We have disrupted the sek1 gene in mice using homologous recombination. Sek1(-/- )embryos display severe anemia and die between embryonic day 10.5 (E10.5) and E12.5. Haematopoiesis from yolk sac precursors and vasculogenesis are normal in sek1(-/- )embryos. However, hepatogenesis and liver formation were severely impaired in the mutant embryos and E11.5 and E12.5 sek1(-/- )embryos had greatly reduced numbers of parenchymal hepatocytes. Whereas formation of the primordial liver from the visceral endoderm appeared normal, sek1(-/-) liver cells underwent massive apoptosis. These results provide the first genetic link between stress-responsive kinases and organogenesis in mammals and indicate that SEK1 provides a crucial and specific survival signal for hepatocytes.


Scaffolded spheroids as building blocks for bottom-up cartilage tissue engineering show enhanced bioassembly dynamics.
Due to the capability of cell spheroids (SPH) to assemble into large high cell density constructs, their use as building blocks attracted a lot of attention in the field of biofabrication. Nevertheless, upon maturation, the composition along with the size of such building blocks change, affecting their fusiogenic ability to form a cohesive tissue construct of controllable size. This natural phenomenon remains a limitation for the standardization of spheroid-based therapies in the clinical setting. We recently showed that scaffolded spheroids (S-SPH) can be produced by forming spheroids directly within porous PCL-based microscaffolds fabricated using multiphoton lithography. In this new study, we compare the bioassembly potential of conventional SPHs versus S-SPHs depending on their degree of maturation. Doublets of both types of building blocks were cultured and their fusiogenicity was compared by measuring the intersphere angle, the length of the fusing spheroid pairs (referred to as doublet length) as well as their spreading behaviour. Finally, the possibility to fabricate macro-sized tissue constructs (i.e. cartilage-like) from both chondrogenic S-SPHs and SPHs was analyzed. This study revealed that, in contrast to conventional SPHs, S-SPHs exhibit robust and stable fusiogenicity, independently from their degree of maturation. In order to understand this behavior, we further analyze the intersection area of doublets, looking at the kinetic of cell migration and at the mechanical stability of the formed tissue using dissection measurement. Our findings indicate that the presence of microscaffolds enhances the ability of spheroids to be used as building blocks for bottom-up tissue engineering, which is an important advantage compared to conventional spheroid-based therapy approaches. STATEMENT OF SIGNIFICANCE: : The approach of using SPHs as building blocks for bottom-up tissue engineering offers a variety of advantages. At the same time the self-assembly of large tissues remains challenging due to several intrinsic properties of SPHs, such as for instance the shrinkage of tissues assembled from SPHs, or the reduced fusiogenicity commonly observed with mature SPHs. In this work, we demonstrate the capability of scaffolded spheroids (S-SPH) to fuse and recreate cartilage-like tissue constructs despite their advanced maturation stage. In this regard, the presence of microscaffolds compensates for some of the intrinsic limitations of SPHs and can help to overcome current limitations of spheroid-based tissue engineering.


Molecular basis of the regulation of Beclin 1-dependent autophagy by the gamma-herpesvirus 68 Bcl-2 homolog M11.
Gamma-herpesviruses (gammaHVs), including important human pathogens such as Epstein Barr virus, Kaposi's sarcoma-associated HV, and the murine gammaHV68, encode homologs of the antiapoptotic, cellular Bcl-2 (cBcl-2) to promote viral replication and pathogenesis. The precise molecular details by which these proteins function in viral infection are poorly understood. Autophagy, a lysosomal degradation pathway, is inhibited by the interaction of cBcl-2s with a key autophagy effector, Beclin 1, and can also be inhibited by gammaHV Bcl-2s. Here we investigate the gammaHV68 M11-Beclin 1 interaction in atomic detail, using biochemical and structural approaches. We show that the Beclin 1 BH3 domain is the primary determinant of binding to M11 and other Bcl-2s, and this domain binds in a hydrophobic groove on M11, reminiscent of the binding of different BH3 domains to other Bcl-2s. Unexpectedly, regions outside of, but contiguous with, the Beclin 1 BH3 domain also contribute to this interaction. We find that M11 binds to Beclin 1 more strongly than do KSHV Bcl-2 or cBcl-2. Further, the differential affinity of M11 for different BH3 domains is caused by subtle, yet significant, variations in the atomic details of each interaction. Consistent with our structural analysis, we find that Beclin 1 residues L116 and F123, and M11 residue pairs G86 + R87 and Y60 + L74, are required for M11 to bind to Beclin 1 and downregulate autophagy. Thus, our results suggest that M11 inhibits autophagy through a mechanism that involves the binding of the Beclin 1 BH3 domain in the M11 hydrophobic surface groove.


DNA adducts and combinations of multiple lung cancer at-risk alleles in environmentally exposed and smoking subjects.
Interindividual variation in DNA adduct levels in individuals exposed to similar amounts of environmental carcinogens may be due to genetic variability. We analysed the influence of genes involved in determining/modifying DNA damage, including microsomal epoxide hydrolase1 (EPHX1) His139Arg, N-acetyl-transferase, NAD(P)H:quinone oxidoreductase1 (NQO1) Pro187Ser, manganese superoxide dismutase2 (MnSOD2) Val16Ala, and apurinic/apyrimidinic endonuclease1 (APE1) Asp148Glu polymorphisms in blood of 120 smokers. Subsequently, we examined the effects of the combinations of the variant alleles of EPHX, NQO1 and MnSOD2 together with the wild type allele of APE1 on DNA damage by calculating the "sum of at-risk alleles." We reviewed the studies examining the relationships of DNA adducts with at-risk alleles in environmentally exposed subjects. Our findings showed that smokers carrying the EPHX1-139Arg and the NQO1-187Ser variants were significantly more likely to have higher adduct levels. Null associations were found with the other variants. Nevertheless, DNA adduct levels in smokers with ≥5 at-risk alleles were significantly different from those with fewer than two alleles. A similar picture emerged from studies of DNA adducts and at-risk alleles in environmentally exposed and smoking subjects. Certain at-risk allele combinations may confer a greater likelihood of increased levels of adducts after environmental insults. The increase in DNA adduct levels in susceptible subjects exposed to environmental carcinogens may reflect changes in the mechanisms that protect cells from the accumulation of genetic damage. Alterations of the physiological processes designed to maintain homeostasis may reduce the individual "genotoxic tolerance" to environmental challenges and result in phenotypes characterized by high levels of DNA adducts.


A commercially available assay kit for determining aldosterone concentration in non-extracted rat serum.
A commercially available assay for aldosterone that requires no extraction was found to be valid without modification for rat serum. The assay was performed in duplicate on as little as 0.5 cc of rat serum and gave linear results from 5 ng/dl to 500 ng/dl, (i.e., the physiological range of the rat). Samples above 150 ng/dl had to be diluted in this assay. The cost per sample if performed in duplicate and in batches was approximately one dollar. We found that this assay, which was developed for and is marketed for determining aldosterone concentration in human samples, offered a cost effective assay for aldosterone determination in the rat.


17β-Hydroxysteroid dehydrogenase type 14 is a predictive marker for tamoxifen response in oestrogen receptor positive breast cancer.
17β-Hydroxysteroid dehydrogenases (17βHSDs) are important enzymes regulating the pool of bioactive steroids in the breast. The current study was undertaken in order to evaluate implications of 17βHSD14 in breast cancer, measuring 17βHSD14 protein expression in breast tumours. An antibody targeting the 17βHSD14 antigen was generated and validated using HSD17B14-transfected cells and a peptide-neutralising assay. Tissue microarrays with tumours from 912 post-menopausal women diagnosed with lymph node-negative breast cancer, and randomised to adjuvant tamoxifen or no endocrine treatment, were analysed for 17βHSD14 protein expression with immunohistochemistry. Results were obtained from 847 tumours. Patients with oestrogen positive tumours with high 17βHSD14 expression had fewer local recurrences when treated with tamoxifen (HR 0.38; 95% C.I. 0.19-0.77, p = 0.007) compared to patients with lower tumoural 17βHSD14 expression, for whom tamoxifen did not reduce the number of local recurrences (HR 1.19; 95% C.I. 0.54-2.59; p = 0.66). No prognostic importance of 17βHSD14 was seen for systemically untreated patients. Using a highly specific validated antibody for immunohistochemical analysis of a large number of breast tumours, we have shown that tumoural expression levels of 17βHSD14 can predict the outcome of adjuvant tamoxifen treatment in terms of local recurrence-free survival in patients with lymph node-negative ER+ breast cancer. The results need be verified to confirm any clinical relevance.


Assessment of temporal variation for the risk of particulate matters on asthma hospitalization.
Increased ambient concentration of particulate matters are considered as one of major causes for increased prevalence or exacerbation of asthma or asthma like symptoms. Recently, possible temporal variation in risks of PM on mortality has been suggested. We investigated short-term effect of both PM10 and PM2.5 on asthma hospitalization, and assessed temporal variation of PM risks in Seoul, Korea, 2003-2011. Generalized additive model was used to estimate PM risks on asthma hospitalization with consideration by long-term trend, influenza epidemic, day of week, meteorological factors. To assess temporal variation of PM risks, year-round PM risks were estimated. Stratified analysis by season and age-group were also conducted. Estimated RRs of PM on asthma hospitalization by an increase of 10㎍/㎥were 1.0084 (95% CI: 1.0041-1.0127) and 1.0156 (95% CI: 1.0055-1.0259) respectively with 7-days lag periods (lag06). PM2.5 had stronger effect than PM10 for all age group. Elderly group was most affected by PM. For the analysis of temporal variation of PM risks, we found increasing trend in total population and the elderly group. In the season-specific analysis, we also found increasing trend in winter for PM10, and in spring for PM2.5. PM10 and PM2.5 has adverse effect on asthma hospitalization with evidence suggesting temporal variation in PM risks. Further research will be needed to confirm the temporal variation of PM risk on asthma hospitalization, and to identify casual factors affecting this temporal variation. This study results could be evidentiary materials for establishing valid public health policies to reduce health burden or economic burden of asthma.


Impact of heat stress on genetic evaluation of oocyte and embryo production in Gir dairy cattle.
Identifying and selecting genotypes tolerant to heat stress might improve reproductive traits in dairy cattle, including oocyte and embryo production. The temperature-humidity index (THI) was used, via random regression models, to investigate the impact of heat stress on genetic parameters and breeding values of oocyte and embryo production in Gir dairy cattle. We evaluated records of total oocytes (TO), viable oocytes (VO), cleaved embryos (CE), and viable embryos (VE) from dairy Gir donors. Twenty-four models were tested, considering age at ovum pick-up (AOPU) and THI means as a regressor in the genetic evaluation. We computed THI in eight periods, from 0 to 112 days before ovum pick-up, which were adjusted by different orders of Legendre polynomials (second, third, and fourth). The best-fit model according to Akaike's information criterion (AIC) and Model Posterior Probabilities (MPP) considered Legendre polynomials of third order and THI means of 112 days for TO, fourth order and 56 days for VO, second order and 28 days for CE, and second order and 42 days for VE, respectively. The heritability (h2) estimates across AOPU and THI scales ranged from 0.34 to 0.62 for TO, 0.31 to 0.58 for VO, 0.26 to 0.39 for CE, and 0.15 to 0.26 for VE, respectively. The fraction of the phenotypic variance explained by the permanent environment in different AOPU and THI scales ranged from 0.03 to 0.25 for TO, 0.05 to 0.26 for VO, 0.09 to 0.36 for CE, and 0.15 to 0.27 for VE, respectively. Spearman's rank correlation between the estimated breeding values in different AOPU and THI scale from the top 5% sires and females ranged from 0.18 to 0.90 for TO, 0.31 to 0.95 for VO, 0.14 to 0.85 for CE, and 0.47 to 0.94 for VE, respectively. The h2 estimates for all evaluated traits varied from moderate to high magnitude across AOPU and THI scales, indicating that genetic selection can result in rapid genetic progress for the evaluated traits. There was a reranking among the best animals in different AOPU and THI. It is possible to select dairy Gir cattle tolerant to heat stress to improve oocyte and embryo production.


Scaffolding depth cues and perceptual learning in VR to train stereovision: a proof of concept pilot study.
Stereopsis is a valuable feature of human visual perception, which may be impaired or absent in amblyopia and/or strabismus but can be improved through perceptual learning (PL) and videogames. The development of consumer virtual reality (VR) may provide a useful tool for improving stereovision. We report a proof of concept study, especially useful for strabismic patients and/or those with reduced or null stereoacuity. Our novel VR PL strategy is based on a principled approach which included aligning and balancing the perceptual input to the two eyes, dichoptic tasks, exposure to large disparities, scaffolding depth cues and perception for action. We recruited ten adults with normal vision and ten with binocular impairments. Participants played two novel PL games (DartBoard and Halloween) using a VR-HMD. Each game consisted of three depth cue scaffolding conditions, starting with non-binocular and binocular cues to depth and ending with only binocular disparity. All stereo-anomalous participants improved in the game and most (9/10) showed transfer to clinical and psychophysical stereoacuity tests (mean stereoacuity changed from 569 to 296 arc seconds, P < 0.0001). Stereo-normal participants also showed in-game improvement, which transferred to psychophysical tests (mean stereoacuity changed from 23 to a ceiling value of 20 arc seconds, P = 0.001). We conclude that a VR PL approach based on depth cue scaffolding may provide a useful method for improving stereoacuity, and the in-game performance metrics may provide useful insights into principles for effective treatment of stereo anomalies.This study was registered as a clinical trial on 04/05/2010 with the identifier NCT01115283 at ClinicalTrials.gov.


Occupant Kinematics in Laboratory Rollover Tests: PMHS Response.
The objective of the current study was to characterize the whole-body kinematic response of restrained PMHS in controlled laboratory rollover tests. A dynamic rollover test system (DRoTS) and a parametric vehicle buck were used to conduct 36 rollover tests on four adult male PMHS with varied test conditions to study occupant kinematics during the rollover event. The DRoTS was used to drop/catch and rotate the test buck, which replicated the occupant compartment of a typical mid-sized SUV, around its center of gravity without roof-to-ground contact. The studied test conditions included a quasi-static inversion (4 tests), an inverted drop and catch that produced a 3 g vertical deceleration (4 tests), a pure dynamic roll at 360 degrees/second (11 tests), and a roll with a superimposed drop and catch produced vertical deceleration (17 tests). Each PMHS was restrained with a three-point belt and was tested in both leading-side and trailing-side front-row seating positions. Whole-body kinematics were measured using a 3D motion capture system that quantified occupant displacement relative to the vehicle buck for the X-axis (longitudinal), Y-axis (lateral), and Z-axis (vertical) directions. Additionally the spine was divided into five segments to describe intrasegmental kinematics of the spine, including segment rotations as well as spinal extension and compression. The reported data represent the most complete set of kinematic response targets for a restrained occupant in a variety of dynamic rollover conditions, and are immediately useful for efforts to evaluate and improve existing ATDs and computational models for use in the rollover crash environment.


The RB1 Mutation Spectrum and Genetic Management Consultation in Pediatric Patients with Retinoblastoma in Beijing, China.
The present study screened the structural mutations of the retinoblastoma (RB1) gene using gene capture and a preliminary exploration of the correlation between the genotypes and phenotypes. A total of 45 formalin-fixed paraffin-embedded (FFPE) tissue samples and 12 peripheral venous blood samples from patients with retinoblastoma (RB) confirmed by pathological examination at Beijing Tongren Hospital were collected between May 2019 and May 2021. DNA from the samples was extracted, sequenced, and analyzed to detect the mutations in the RB1 gene by designing the targeted capture probes for exons and the flanking sequences of the gene. Of the 45 FFPE tissue samples, 23 were from male patients and 22 were from female patients, all aged between 4 months and 10 years, with an average age of 2.5 ± 1.3 years. Two of these patients had bilateral RB and 43 had unilateral RB (23 in the right eye and 20 in the left eye). Of the 12 peripheral venous blood samples, 7 were from male patients and 5 were from female patients, all aged between 8 months and 4 years, with an average age of 1.3 ± 0.9 years. Two of these patients had bilateral RB and 10 had unilateral RB (8 in the right eye and 2 in the left eye). Three de novo pathogenic mutations were found in the FFPE tissues, along with one de novo potentially pathogenic mutation, while three de novo potentially pathogenic mutations were found in the blood samples. Gene capture is a low-cost and efficient method for the gene sequencing of RB. A total of seven de novo mutations were identified through mutation testing of the pathogenic gene RB1 in 56 pediatric patients with RB. This complemented the mutation spectrum of the RB1 gene and helped to improve the molecular diagnosis of RB, thereby providing a basis for genetic counseling and prediction of the clinical phenotype, as well as for the genetic testing of the offspring of patients with RB. ChiCTR-EPC-17013892.


Natural Product-based Nanomedicine: Recent Advances and Issues for the Treatment of Alzheimer's Disease.
Alzheimer's disease (AD) affects the elderly and is characterized by progressive neurodegeneration caused by different pathologies. The most significant challenges in treating AD include the inability of medications to reach the brain because of its poor solubility, low bioavailability, and the presence of the blood-brain barrier (BBB). Additionally, current evidence suggests the disruption of BBB plays an important role in the pathogenesis of AD. One of the critical challenges in treating AD is the ineffective treatments and their severe adverse effects. Nanotechnology offers an alternative approach to facilitate the treatment of AD by overcoming the challenges in drug transport across the BBB. Various nanoparticles (NP) loaded with natural products were reported to aid in drug delivery for the treatment of AD. The nano-sized entities of NP are great platforms for incorporating active materials from natural products into formulations that can be delivered effectively to the intended action site without compromising the material's bioactivity. The review highlights the applications of medicinal plants, their derived components, and various nanomedicinebased approaches for the treatment of AD. The combination of medicinal plants and nanotechnology may lead to new theragnostic solutions for the treatment of AD in the future.


Factors affecting bone mineral density in multiple sclerosis patients.
Multiple sclerosis (MS) is a demyelinating disease which can cause many disabilities for the patient. Recent data suggests that MS patients have higher risk for osteoporosis. This study was performed to investigate if the osteoporosis prevalence is higher in MS patients and to determine the possible factors affecting bone mineral density (BMD). 51 definite relapsing-remitting MS patients according to McDonald's criteria (45 females, 6 males aged between 20 and 50 years) participated in this study. The control group included 407 females aged from 20 to 49 years; they were healthy and had no history of the diseases affecting bone metabolism. Femoral and lumbar BMD were measured by Dual Energy X-ray Absorptiometry (DXA). The disability of MS patients was evaluated by Expanded Disability Status Scale (EDSS). The patient's quality of life was evaluated by the validated Persian version of multiple sclerosis impact scale (MSIS-29). Patients' mean age was 36 ± 3.3 years and their mean disease duration was 8.7 ± 1.7 years. The mean EDSS score and the mean body mass index (BMI) of the patients were 3 ± 0.9 and 23.5 ± 2.3 kg/m(2), respectively. 29% of the patients had never been treated by ß-interferon and 6% of them had not received glucocorticoids (GCs) pulses since their MS had been diagnosed. 26% of the patients had a history of fracture.18% of our patients were osteoporotic and 43% of them were osteopenic. Femoral BMD was significantly lower among MS patients than age matched controls (P < 0.001), but lumbar BMD showed no difference. There was no correlation between administration of GCs pulses, interferon and BMD; however, we found a significant correlation between EDSS score, quality of life (QoL), disease duration and BMD of both site. As a result of this study, bone loss inevitably occurs in MS patients. The major factor of BMD loss is immobility. Osteoporosis should be managed as part of MS patients' treatment protocols.


Assessment of learning abilities using complex experimental learning tasks.
Efforts are underway to develop a computerized methodology for the reliable, valid measurement of learning abilities. Central to these research efforts are the development of Complex Experimental Learning Tasks (CELTs) that provide real-time samples of learning. Objectives of current studies are the determination of relationships between performance on CELTs and performance on traditional cognitive abilities tests and the exploration of predictive value of measures of learning ability for academic performance. After construct and predictive validity are established, this methodology may be applicable to a wide range of assessment situations, including testing for the effects of environmental toxicants on learning abilities.


Trajectories of low back pain.
Low back pain is not a self-limiting problem, but rather a recurrent and sometimes persistent disorder. To understand the course over time, detailed investigation, preferably using repeated measurements over extended periods of time, is needed. New knowledge concerning short-term trajectories indicates that the low back pain 'episode' is short lived, at least in the primary care setting, with most patients improving. Nevertheless, in the long term, low back pain often runs a persistent course with around two-thirds of patients estimated to be in pain after 12 months. Some individuals never have low back pain, but most have it on and off or persistently. Thus, the low back pain 'condition' is usually a lifelong experience. However, subgroups of patients with different back pain trajectories have been identified and linked to clinical parameters. Further investigation is warranted to understand causality, treatment effect and prognostic factors and to study the possible association of trajectories with pathologies.


Hybrid endovascular and off-pump open surgical treatment for synchronous aneurysms of the aortic arch, brachiocephalictrunk, and abdominal aorta.
A 71-year-old patient was admitted for synchronous aneurysms of the aortic arch, brachiocephalic trunk, and juxtarenal abdominal aorta involving the iliac arteries. The patient first underwent open surgical repair of the juxtarenal abdominal aortic aneurysm by means of aorto-bifemoral bypass. Three months later, he underwent off-pump surgical repair of the aneurysm of the brachiocephalic trunk and bypass grafting from the ascending aorta to the brachiocephalic trunk and the left common carotid artery, followed by successful exclusion of the aneurysm of the aortic arch by deployment of a Zenith TX1 custom-made endograft, inserted through a limb of the aorto-bifemoral graft. Combined endovascular and open surgical treatment is an appealing new alternative to open surgical repair for complex aortic diseases. Debranching of the aortic arch enables endovascular grafting in this area, thereby avoiding cardiopulmonary bypass and circulatory arrest. Staged and simultaneous procedures should be considered for the treatment of complex aortic diseases even in poor-risk patients; however due to the investigative characteristics of these procedures, patient selection and postoperative follow-up should be carried out with utmost attention.


Dicopper(II) metallacyclophanes with oligo(p-phenylene-ethynylene) spacers: experimental foundations and theoretical predictions on potential molecular magnetic wires.
Two novel double-stranded dicopper(II) metallacyclophanes of formula (nBu4N)4[Cu2(dpeba)2]·4MeOH·2Et2O (1) and (nBu4N)4[Cu2(tpeba)2]·12H2O (2) have been prepared by the Cu(II)-mediated self-assembly of the rigid ('rod-like') bridging ligands N,N'-4,4'-diphenylethynebis(oxamate) (dpeba) and N,N'-1,4-di(4-phenylethynyl)phenylenebis(oxamate) (tpeba), respectively. Single crystal X-ray diffraction analysis of 1 confirms the presence of a dicopper(II)tetraaza[3.3]4,4'-diphenylethynophane metallacyclic structure featuring a very long intermetallic distance between the two square planar Cu(II) ions [r = 14.95(1) Å]. The overall parallel-displaced π-stacked conformation of the two nearly planar para substituted diphenylethyne spacers [dihedral angle (ψ) of 7.8(1)°] leads to important deviations from the perpendicular orientation of the copper mean basal planes with respect to the facing benzene planes [dihedral angles (φ) of 56.4(1) and 58.4(1)°]. X-band EPR spectra together with variable-temperature magnetic susceptibility and variable-field magnetization measurements of 1 and 2, both in solution and in the solid state, show the occurrence of a non-negligible, moderate to weak intramolecular antiferromagnetic coupling [-J = 3.9-4.1 (1) and 0.5-0.9 cm(-1) (2); H = -JS1·S2 with S1 = S2 = SCu = 1/2]. Density functional calculations on the BS singlet (S = 0) and triplet (S = 1) spin states of the model complexes 1 and 2 with an ideal orthogonal molecular geometry (ψ = 0° and φ = 90°) support the occurrence of a spin polarization mechanism for the propagation of the exchange interaction between the two unpaired electrons occupying the dxy orbital of each square planar Cu(II) ion through the predominantly π-type orbital pathway of the double p-diphenylethyne (1) and di(phenylethynyl)phenylene spacers (2). Time-dependent density functional calculations reproduce the observed bathochromic shift of the main intraligand (IL) π-π* transition in the electronic absorption spectra of 1 and 2 [λ1 = 308 (1) and 316 nm (2)]. In the series of orthogonal model complexes 1-5 with linear oligo(p-phenylene-ethynylene) (OPE) spacers, -C6H4(C≡CC6H4)n- (n = 1-5), a linear increase of the IL π-π* transition energy with the reciprocal of the intermetallic distance is theoretically predicted [νmax = 1.99 × 10(4) + 2.15 × 10(5) (1/r) (S = 0) or ν = 2.01 × 10(4) + 2.18 × 10(5) (1/r) (S = 1)], which clearly indicates that the effective π-conjugation length increases with the number of phenylethyne repeating units. This is accompanied by an exponential decay of the antiferromagnetic coupling with the intermetallic distance [-J = 1.08 × 10(3) exp(-0.31r)], which supports the ability of the extended π-conjugated OPEs to mediate the exchange interaction between the unpaired electrons of the two Cu(II) centers with intermetallic distances in the range of 1.5-4.3 nm. Further developments may be then envisaged for this new family of oxamato-based dicopper(II) oligo-p-phenylethynophanes on the basis of the unique ligand capacity to act as a molecular antiferromagnetic wire.


Alveolar ridge augmentation using nonresorbable hydroxylapatite with or without autogenous cancellous bone.
A four-year prospective evaluation of the use of nonresorbable, particulate hydroxylapatite (HA) to augment deficient alveolar ridges was performed. The material was used alone and in combination with finely crushed autogenous cancellous bone. Implants were delivered subperiosteally by syringe injection, usually using local anesthesia for Class I to Class III ridges and general anesthesia for Class III and Class IV ridges. The improved ridge height and width were stable. Postoperative resorption with significant loss of ridge height, frequently seen with rib and iliac crest onlayed grafts, was not observed with HA augmentation. Permanent denture construction began as early as three weeks postoperatively and by four to six weeks if HA was combined with autogenous cancellous bone. It was possible to place mandibular staple implants simultaneously or following HA augmentation. Visor osteotomy techniques were improved by use of HA to produce a wider, more convex stable ridge. Although skin, mucosa, or dermal vestibuloplasties were performed as early as three months postoperatively in a small number of patients, there appeared to be a lesser need for vestibuloplasty after HA augmentation than after onlay bone grafting. In addition, prosthodontists performed fewer denture relines after HA augmentation than after onlay bone grafts. The authors believe the most significant factor accounting for these observations is the firm, nonmobile mucosal base resulting from augmentation with HA. The resultant stable, soft tissue base and improved ridge height and contour have contributed to a comfortable, retentive, stable denture for these patients. The prosthetic and surgical procedures are easier to perform and have produced superior, more permanent results than onlay bone grafts and alloplasts. Preliminary studies also point to exciting possibilities for use of HA as a bone substitute/marrow extender in maxillary and mandibular defects, cysts, and clefts and in osteotomies for orthognathic surgery.


Soybean flower-to-seed movement of epiphytic bacteria.
Epiphytic tracer bacteris (a Pseudomonas sp. and an Arthrobacter sp.) from soybean buds were introduced into open flowers of greenhouse-grown soybean plants. Of the 177 resulting pods cultured after surface disinfection, tracers were recovered from within 24. Seed from two of these pods also carried tracers.


Current applications of nanotechnology to develop plant growth inducer agents as an innovation strategy.
Nanotechnology has been proposed as an important tool and strategy for applying new products in agriculture at the nanometer scale in order to improve the food crop at sustainability and productivity levels for contributing with the agriculture security. Nanoparticles (NPs) have been planted as an intelligent material with a large contact surface per unit mass respect to bulk-products, allowing its effect to be exerted with greater efficiency in a specific point on a plant target. Currently, NPs have been studied to be applied to various species of monocotyledonous and dicotyledonous plants. Some NPs properties such as concentration, shape, size, composition and surface functionality have the ability to regulate the NPs growth effects on the plant during germination and seedling stages under controlled and field conditions. Furthermore, several studies have tried to explain the mechanism of uptake, translocation and accumulation of NPs inside the plant at the organ and cell level, but further studies are needed to determine specific mechanisms and exact action. Nevertheless, evaluation of the toxicity effects of NPs on physiological indexes of the plant is needed to determine the effective dose without producing adverse effects on the plant and food chain. It is noteworthy that studies have indicated that nanoparticles, regardless of their nature, can be efficient inducers of plant growth. However, a series of laboratory tests are required to optimize their application conditions and their specific physiological impact on plants. In this review, we summarize the knowledge about NPs application to induce plant growth to direct future studies in order to propose NPs for technological innovation.


Fifteen years of using a second stage protein substitute for weaning in phenylketonuria: a retrospective study.
In phenylketonuria (PKU), during weaning, it is necessary to introduce a second stage phenylalanine (Phe)-free protein substitute (PS) to help meet non-Phe protein requirements. Semi-solid weaning Phe-free PS have been available for >15 years, although no long-term studies have reported their efficacy. Retrospective data from 31 children with PKU who commenced a weaning PS were collected from clinical records from age of weaning to 2 years, on: gender; birth order; weaning age; anthropometry; blood Phe levels; age commenced and dosage of weaning PS and Phe-free infant L-amino acid formula; natural protein intake; and issues with administration of PS or food. Median commencement age for weaning was 17 weeks (range 12-25 weeks) and, for weaning PS, 20 weeks (range 13-37 weeks). Median natural protein was 4 g day-1 (range 3-11 g day-1 ) and total protein intake was >2 g kg-1 day-1 from weaning to 2 years of age. Children started on 2-4 g day-1 protein equivalent (5-10 g day-1 of powder) from weaning PS, increasing by 0.2 g kg-1 day-1 (2 g day-1 ) monthly to 12 months of age. Teething and illness adversely affected the administration of weaning PS and the acceptance of solid foods. Altogether, 32% of children had delayed introduction of more textured foods, associated with birth order (firstborn 80% versus 38%; P = 0.05) and food refusal when teething (80% versus 29%; P = 0.02). Timing of introduction of solid foods and weaning PS, progression onto more textured foods and consistent feeding routines were important in aiding their acceptance. Any negative behaviour with weaning PS was mainly associated with food refusal, teething and illness. Parental approach influenced the acceptance of weaning PS.


Coronary artery calcification compared with carotid intima-media thickness in the prediction of cardiovascular disease incidence: the Multi-Ethnic Study of Atherosclerosis (MESA).
Coronary artery calcium (CAC) and carotid intima-media thickness (IMT) are noninvasive measures of atherosclerosis that consensus panels have recommended as possible additions to risk factor assessment for predicting the probability of cardiovascular disease (CVD) occurrence. Our objective was to assess whether maximum carotid IMT or CAC (Agatston score) is the better predictor of incident CVD. A prospective cohort study of subjects aged 45 to 84 years in 4 ethnic groups, who were initially free of CVD (n = 6698) was performed, with standardized carotid IMT and CAC measures at baseline, in 6 field centers of the Multi-Ethnic Study of Atherosclerosis (MESA). The main outcome measure was the risk of incident CVD events (coronary heart disease, stroke, and fatal CVD) over a maximum of 5.3 years of follow-up. There were 222 CVD events during follow-up. Coronary artery calcium was associated more strongly than carotid IMT with the risk of incident CVD. After adjustment for each other (CAC score and IMT) and age, race, and sex [corrected], the hazard ratio of CVD increased 2.1-fold (95% confidence interval [CI], 1.8-2.5) for each 1-standard deviation (SD) increment of log-transformed CAC score, vs 1.3-fold (95% CI, 1.1-1.4) for each 1-SD increment of the maximum IMT. For coronary heart disease, the hazard ratios per 1-SD increment increased 2.5-fold (95% CI, 2.1-3.1) for CAC score and 1.2-fold (95% CI, 1.0-1.4) for IMT. A receiver operating characteristic curve analysis also suggested that CAC score was a better predictor of incident CVD than was IMT, with areas under the curve of 0.81 vs 0.78, respectively. Although whether and how to clinically use bioimaging tests of subclinical atherosclerosis remains a topic of debate, this study found that CAC score is a better predictor of subsequent CVD events than carotid IMT.


Traumatic brain injury and schizophrenia in members of schizophrenia and bipolar disorder pedigrees.
Schizophrenia following a traumatic brain injury could be a phenocopy of genetic schizophrenia or the consequence of a gene-environment interaction. Alternatively, traumatic brain injury and schizophrenia could be spuriously associated if those who are predisposed to develop schizophrenia have greater amounts of trauma for other reasons. The authors investigated the relationship between traumatic brain injury and psychiatric diagnoses in a large group of subjects from families with at least two biologically related first-degree relatives with schizophrenia, schizoaffective disorder, or bipolar disorder. The Diagnostic Interview for Genetic Studies was used to determine history of traumatic brain injury and diagnosis for 1,275 members of multiplex bipolar disorder pedigrees and 565 members of multiplex schizophrenia pedigrees. Rates of traumatic brain injury were significantly higher for those with a diagnosis of schizophrenia, bipolar disorder, and depression than for those with no mental illness. However, multivariate analysis of within-pedigree data showed that mental illness was related to traumatic brain injury only in the schizophrenia pedigrees. Independent of diagnoses, family members of those with schizophrenia were more likely to have had traumatic brain injury than were members of the bipolar disorder pedigrees. The members of the schizophrenia pedigrees also failed to show the gender difference for traumatic brain injury (more common in men than in women) that was expected and was present in the bipolar disorder pedigrees. Subjects with a schizophrenia diagnosis who were members of the bipolar disorder pedigrees (and thus had less genetic vulnerability to schizophrenia) were less likely to have had traumatic brain injury (4.5%) than were subjects with schizophrenia who were members of the schizophrenia pedigrees (and who had greater genetic vulnerability to schizophrenia) (19.6%). Members of the schizophrenia pedigrees, even those without a schizophrenia diagnosis, had greater exposure to traumatic brain injury compared to members of the bipolar disorder pedigrees. Within the schizophrenia pedigrees, traumatic brain injury was associated with a greater risk of schizophrenia, consistent with synergistic effects between genetic vulnerability for schizophrenia and traumatic brain injury. Posttraumatic-brain-injury schizophrenia in multiplex schizophrenia pedigrees does not appear to be a phenocopy of the genetic disorder.


Characteristics of first-time fathers of advanced age: a Norwegian population-based study.
The modern phenomenon of delayed parenthood applies not only to women but also to men, but less is known about what characterises men who are expecting their first child at an advanced age. This study investigates the sociodemographic characteristics, health behaviour, health problems, social relationships and timing of pregnancy in older first-time fathers. A cross-sectional study was conducted of 14 832 men who were expecting their first child, based on data from the Norwegian Mother and Child Cohort Study (MoBa) carried out by the Norwegian Institute of Public Health. Data were collected in 2005-2008 by means of a questionnaire in gestational week 17-18 of their partner's pregnancy, and from the Norwegian Medical Birth Register. The distribution of background variables was investigated across the age span of 25 years and above. Men of advanced age (35-39 years) and very advanced age (40 years or more) were compared with men aged 25-34 years by means of bivariate and multivariate logistic regression analyses. The following factors were found to be associated with having the first child at an advanced or very advanced age: being unmarried or non-cohabitant, negative health behaviour (overweight, obesity, smoking, frequent alcohol intake), physical and mental health problems (lower back pain, cardiovascular diseases, high blood pressure, sleeping problems, previous depressive symptoms), few social contacts and dissatisfaction with partner relationship. There were mixed associations for socioeconomic status: several proxy measures of high socioeconomic status (e.g. income >65,000 €, self-employment) were associated with having the first child at an advanced or very advanced age, as were several other proxy measures of low socioeconomic status (e.g. unemployment, low level of education, immigrant background).The odds of the child being conceived after in vitro fertilisation were threefold in men aged 34-39 and fourfold from 40 years and above. Men who expect their first baby at an advanced or very advanced age constitute a socioeconomically heterogeneous group with more health problems and more risky health behaviour than younger men. Since older men often have their first child with a woman of advanced age, in whom similar characteristics have been reported, their combined risk of adverse perinatal outcomes needs further attention by clinicians and researchers.


Prevalence of VKORC1 and CYP2C9 gene polymorphisms in Indian population and its effect on warfarin response.
The clinical effectiveness of Warfarin is established. Patients require different warfarin dosages to achieve the target therapeutic anticoagulation. The variability of Warfarin dosage is largely genetically determined, and it can be partly explained by the C1173T and G-1639A polymorphisms of vitamin K epoxide reductase complex subunit 1 (VKORC1) which is its target and *2 and *3 allele of Cytochrome P-450 (CYP) 2C9 [CYP2C9] enzyme which metabolizes to its inactive form. Aim of the present study was to determine the prevalence of these variant alleles known to influence the warfarin dose and correlate genotypes with the average INR as well as mean dose of Warfarin required to maintain INR, in the Indian population. Study population included 100 healthy individuals and 83 patients operated for Aortic or Mitral Valve replacement and prescribed warfarin thereafter. Of these 83 patients records of INR for the period of six months and mean maintenance dose (stable therapeutic dose) of warfarin required to maintain INR were available for 26 patients. For the remaining patients, apart from their demographic data only maintenance dose was available. Genotyping of above mentioned polymorphisms was carried out by using PCR-based restriction digestion method. Although less as compared to wild type alleles, the variant alleles of CYP2C9*2 and *3 as well as of VKORC1 polymorphisms (C1173T and G-1639A) were observed in our study population. Mean maintenance dose (mg/day) of Warfarin was in the decreasing order of patients as compared to the wild type genotypes for all above mentioned polymorphisms. The decrease in the dose was in the order of heterozygotes for CYP2C9*2 to CYP2C9*3 to C1173T and G-1639A of VKORC1 (P<0.001). There was significant correlation (r=0.51, P<0.001) observed between the dose estimated by pharmacogenetic algorithm of Sconce et al (2005) and actual stable therapeutic dose. INR was high for mutant variants (3.8 to 4) after first dose suggesting that they require decreased mean daily dose of Warfarin. In the present study the effect of CYP2C9*2, *3, and VKORC1 (C1173T and G-1639A) genotypes on warfarin dose was observed. However, the genotyping has not been incorporated into daily practice. Perhaps more practical approach would be for clinicians to take genotype information into consideration along with other factors when dosing warfarin.


Cardiac myxoma: clinical characteristics, surgical intervention, intra-operative challenges and outcome.
The objectives of this retrospective study were to characterize the clinical presentation, diagnostic findings, surgical approaches, intra-operative challenges and complications following the surgical treatment of cardiac myxoma in two of the largest referral hospitals in Jordan. Medical records of all patients presented to the cardiology department during the period between 1984 and 2016 were reviewed. Criteria for inclusion in the study were: (1) patients who were presented for cardiac evaluation due to symptoms suggestive of a primary cardiac problem, (2) completed medical records, including results of echocardiography suggestive of intra-cardiac occupying mass, (3) the surgical operation was undertaken and intra-operative data was available, (4) a histological diagnosis of myxoma was available and (5) the discharge status and follow-up data were available for at least 2 years after initial surgery. A total of 27 patients fulfilled the criteria for inclusion in the study. The average age was 42 years. Thirteen of the patients were females and 14 patients were males. The most common clinical presentations were dyspnea (29.6%) and murmurs (22.2%). Non-specific signs, such as weight loss, fever, fatigue, arthralgia and anemia, were reported in 10 (37%) patients. Signs related to systemic embolization were reported in 9 (33.3%) of the patients, involving the upper and lower extremities (55.6%), brain ischemia and vision loss (54.4%). Tumors in all patients were successfully resected under cardiopulmonary bypass support. The tumor was pedunculated in 17 (62.9%) of the patients and the size of the tumors varied from 1 to 7 centimeters in diameter. The tumor was located in the left atrium in 21 patients (77.7%), in the right atrium in 4 patients (14.8%), in the right ventricular side of the septum in 1 patient (3.7%) and involving the tricuspid valve in 1 patient (3.7%). The left atrial approach was used in 3 patients, a right atrial approach in 4 patients and a bi-atrial approach in 20 patients. The most common concomitant cardiac pathology was coronary artery disease in 3 patients and an atrial septal defect in one patient. The most common intra-operative challenges were inter-atrial communication (2 patients), large defect in the tricuspid valve leaflet (1 patient) and involvement of the inter-ventricular septum (1 patient). In the post-operative period, 1 patient suffered a stroke. In the post-operative period, the most common complications were stroke (1 patient) and recurrence of the tumor (2 patients). The success rate after surgical removal of cardiac myxoma in this study was substantial and complications were rare.


Phylomineralogy of the coralline red algae: correlation of skeletal mineralogy with molecular phylogeny.
The coralline algae in the orders Corallinales and Sporolithales (subclass Corallinophycidae), with their high degree of mineralogical variability, pose a challenge to projections regarding mineralogy and response to ocean acidification. Here we relate skeletal carbonate mineralogy to a well-established phylogenetic framework and draw inferences about the effects of future changes in sea-water chemistry on these calcified red algae. A collection of 191 coralline algal specimens from New Zealand, representing 13 genera and 28 species, included members of three families: Corallinaceae, Hapalidiaceae, and Sporolithaceae. While most skeletal specimens were entirely calcitic (range: 73-100 wt.% calcite, mean 97 wt.% calcite, std dev=5, n=172), a considerable number contained at least some aragonite. Mg in calcite ranged from 10.5 to 16.4 wt.% MgCO(3), with a mean of 13.1 wt.% MgCO(3) (std dev=1.1, n=172). The genera Mesophyllum and Lithophyllum were especially variable. Growth habit, too, was related to mineralogy: geniculate coralline algae do not generally contain any aragonite. Mg content varied among coralline families: the Corallinaceae had the highest Mg content, followed by the Sporolithaceae and the Hapalidiaceae. Despite the significant differences among families, variation and overlap prevent the use of carbonate mineralogy as a taxonomic character in the coralline algae. Latitude (as a proxy for water temperature) had only a slight relationship to Mg content in coralline algae, contrary to trends observed in other biomineralising taxa. Temperate magnesium calcites, like those produced by coralline algae, are particularly vulnerable to ocean acidification. Changes in biomineralisation or species distribution may occur over the next few decades, particularly to species producing high-Mg calcite, as pH and CO(2) dynamics change in coastal temperate oceans.


[Conformational mobility and enzymatic activity of Ca2+-ATPase from sarcoplasmic reticulum].
Purified preparations of Ca2+-dependent ATPase were lipid-deleted and incorporated into egg lecithin (EL) and dipalmitoyl lecithin (DPL) liposomes. The temperature dependences of the catalytic activity and of molecular mobility of the spin label (N-1-hydroxyl-2,2,6,6-tetramethyl-4-piperidyl) maleimide linked to a highly reactive SH-group in the vicinity of the active center (15-16 A) and of the fatty acid spin probe (6-doxylpalmitate) located in the protein-lipid moiety were compared. The molecular mobility of the spin label was measured by the saturation transfer method; that of the spin probe was estimated from the maximal splitting value. It was found that the catalytic activity of DPL is correlated with the molecular mobility of the hydrophobic part of ATPase, while that of EL with the segment flexibility in the vicinity of the active center.


Spin-Flip Unitary Coupled Cluster Method: Toward Accurate Description of Strong Electron Correlation on Quantum Computers.
Quantum computers have emerged as a promising platform to simulate strong electron correlation that is crucial to catalysis and photochemistry. However, owing to the choice of a trial wave function employed in the variational quantum eigensolver (VQE) algorithm, accurate simulation is restricted to certain classes of correlated phenomena. Herein, we combine the spin-flip (SF) formalism with the unitary coupled cluster with singles and doubles (UCCSD) method via the quantum equation-of-motion (qEOM) approach to allow for an efficient simulation of a large family of strongly correlated problems. We show that the developed qEOM-SF-UCCSD/VQE method outperforms its UCCSD/VQE counterpart for simulation of the cis-trans isomerization of ethylene, and the automerization of cyclobutadiene and the predicted qEOM-SF-UCCSD/VQE barrier heights are in a good agreement with the experimentally determined values. The developments presented herein will further stimulate the investigation of this approach for simulations of other types of correlated/entangled phenomena on quantum computers.


Functional analysis of HD2 histone deacetylase homologues in Arabidopsis thaliana.
Post-translational modification of histones, in particular acetylation, is an important mechanism in the regulation of eukaryotic gene expression. Histone deacetylases are enzymes that remove acetyl groups from the core histones and play a key role in the repression of transcription. HD2 is a maize histone deacetylase, which shows no sequence homology to the histone deacetylases identified from other eukaryotes. We have identified two putative HD2-like histone deacetylase cDNA clones, AtHD2A and AtHD2B, from Arabidopsis thaliana by screening the expressed sequence tag database. AtHD2A and AtHD2B encode putative proteins of 246 and 305 amino acids, and share 44% and 46% amino acid identity to the maize HD2, respectively. Northern blot analysis indicated that AtHD2A was highly expressed in flowers and young siliques of Arabidopsis plants, whereas AtHD2B was widely expressed in stems, leaves, flowers and young siliques. AtHD2A repressed transcription when directed to a promoter containing GAL4-binding sites as a GAL4 fusion protein. Deletion of the extended acidic domain or the domain containing predicted catalytic residues of AtHD2A resulted in the loss of gene repression activity, revealing the importance of both domains to AtHD2A function. Arabidopsis plants were transformed with a gene construct comprising an AtHD2A cDNA in the antisense orientation driven by a strong constitutive promoter, -394tCUP. Silencing of AtHD2A expression resulted in aborted seed development in transgenic Arabidopsis plants, suggesting that the AtHD2A gene product was important in the reproductive development of Arabidopsis thaliana.


The kinome of Phytophthora infestans reveals oomycete-specific innovations and links to other taxonomic groups.
Oomycetes are a large group of economically and ecologically important species. Its most notorious member is Phytophthora infestans, the cause of the devastating potato late blight disease. The life cycle of P. infestans involves hyphae which differentiate into spores used for dispersal and host infection. Protein phosphorylation likely plays crucial roles in these stages, and to help understand this we present here a genome-wide analysis of the protein kinases of P. infestans and several relatives. The study also provides new insight into kinase evolution since oomycetes are taxonomically distant from organisms with well-characterized kinomes. Bioinformatic searches of the genomes of P. infestans, P. ramorum, and P. sojae reveal they have similar kinomes, which for P. infestans contains 354 eukaryotic protein kinases (ePKs) and 18 atypical kinases (aPKs), equaling 2% of total genes. After refining gene models, most were classifiable into families seen in other eukaryotes. Some ePK families are nevertheless unusual, especially the tyrosine kinase-like (TKL) group which includes large oomycete-specific subfamilies. Also identified were two tyrosine kinases, which are rare in non-metazoans. Several ePKs bear accessory domains not identified previously on kinases, such as cyclin-dependent kinases with integral cyclin domains. Most ePKs lack accessory domains, implying that many are regulated transcriptionally. This was confirmed by mRNA expression-profiling studies that showed that two-thirds vary significantly between hyphae, sporangia, and zoospores. Comparisons to neighboring taxa (apicomplexans, ciliates, diatoms) revealed both clade-specific and conserved features, and multiple connections to plant kinases were observed. The kinome of Hyaloperonospora arabidopsidis, an oomycete with a simpler life cycle than P. infestans, was found to be one-third smaller. Some differences may be attributable to gene clustering, which facilitates subfamily expansion (or loss) through unequal crossing-over. The large sizes of the Phytophthora kinomes imply that phosphorylation plays major roles in their life cycles. Their kinomes also include many novel ePKs, some specific to oomycetes or shared with neighboring groups. Little experimentation to date has addressed the biological functions of oomycete kinases, but this should be stimulated by the structural, evolutionary, and expression data presented here. This may lead to targets for disease control.


Removal of the organic surface layer in combined sewer sediment using a flushing gate.
Recent research identified the different sources of pollution of wet weather Combined Sewers Overflows (CSOs): it appeared that the deposits in sewers, and especially an organic layer situated at the water-sediment interface, may contribute 40-70% to the total pollution load of CSOs. Using the cyclic flush Hydrass gate, we generated increased water flows during dry weather. The effects of flushing the deposits have been analysed: the eroded particles sampled during the first flush wave show pollutant characteristics similar to characteristics measured in the organic layer. The organic layer that has formed on the surface of deposits can thus be washed off before rainstorms occur using the cyclic flushing technique.


A 32-kD GTP-binding protein associated with the CD4-p56lck and CD8-p56lck T cell receptor complexes.
The guanosine triphosphate (GTP)-binding proteins include signal-transducing heterotrimeric G proteins (for example, Gs, Gi), smaller GTP-binding proteins that function in protein sorting, and the oncogenic protein p21ras. The T cell receptor complexes CD4-p56lck and CD8-p56lck were found to include a 32- to 33-kilodalton phosphoprotein (p32) that was recognized by an antiserum to a consensus GTP-binding region in G proteins. Immunoprecipitated CD4 and CD8 complexes bound GTP and hydrolyzed it to guanosine diphosphate (GDP). The p32 protein was covalently linked to [alpha-32P]GTP by ultraviolet photoaffinity labeling. These results demonstrate an interaction between T cell receptor complexes and an intracellular GTP-binding protein.


Spatiotemporal expression of alternatively spliced IGF-I mRNA in the rat costochondral growth plate.
IGF-I acts as a local proliferation and maturation factor for chondrocytes in the growth plate. However, the expression of different alternative IGF-I mRNA classes in the growth plate has not been characterized. Using quantitative reverse transcription PCR, the abundance of each alternative IGF-I mRNA class in resting, proliferative and hypertrophic chondrocytes was measured in rat costochondral growth plates. Class 1Ea mRNA was the most abundant IGF-I transcript overall and was highly expressed in proliferative chondrocytes at 2 and 4 weeks of age; by 6 weeks, the majority of 1Ea mRNA expression had shifted to hypertrophic chondrocytes. Class 1Eb mRNA was the second most abundant transcript and its distribution was uniform across all the cell types at 2 weeks of age. The expression pattern changed with increasing age such that at 6 weeks a gradient existed with hypertrophic chondrocytes expressing higher levels of 1Eb than resting chondrocytes. Class 2Ea mRNA was constitutively expressed at low levels across the growth plate at all ages, while class 2Eb mRNA expression was negligible. The distribution of total IGF-I mRNA also shifted across growth plate cell types as the animals aged from 2 to 6 weeks. These findings suggest that IGF-I class 1 mRNA plays the predominant role in the maturation of the growth plate.


Evidence that noradrenaline increases pyruvate dehydrogenase activity and decreases acetyl-CoA carboxylase activity in rat interscapular brown adipose tissue in vivo.
The rate of fatty acid synthesis in interscapular brown adipose tissue of female cold-adapted rats, as measured by the incorporation of 3H from 3H2O into tissue lipid, was decreased by about 70% after injection of noradrenaline. There was a similar decrease in the activity of acetyl-CoA carboxylase. In contrast, the proportion of pyruvate dehydrogenase in its active non-phosphorylated form was greatly increased after injection of noradrenaline. This finding suggests that the oxidation of glucose may be important in noradrenaline-induced thermogenesis in rat brown adipose tissue.


Nutrition status of the Chinese people.
Based on the available data collected with national nutritional survey, nutrition surveillance and the child surveys since 1987, analysis on food consumption, dietary pattern and nutrition status of the Chinese people has been done. The data sets used for the analysis are as follows. (1) 1987 Child Survey in 9 Provinces-91,011 preschool children were sampled. (2) 1992 National Child Survey-570,704 children under the age of 15 were sampled, with anthropometric measurement of 185,965 children under the age of 5. (3) 1990 Nutrition Surveillance-State Statistic Bureau (SSB) household survey in selected 7 provinces (including Beijing Municipality) with 8629 household samples in the urban and 11,840 households in the rural covered 5341 children under the age of 6, among which 1487 were in the urban and 3854 in the rural. (4) 1992 Third National Nutritional Survey-All the provinces and municipalities were covered with 25,033 household samples, among which 8474 were in the urban and 16,559 in the rural. 99,749 residents were surveyed, among which 30,723 were in the urban and 69,026 in the rural. Dietary survey data is used for comparison on food consumption and nutrient intake with 1990 nutrition surveillance data.


Active Learning Guided Computational Discovery of Plant-Based Redoxmers for Organic Nonaqueous Redox Flow Batteries.
Organic nonaqueous redox flow batteries (O-NRFBs) are promising energy storage devices due to their scalability and reliance on sourceable materials. However, finding suitable redox-active organic molecules (redoxmers) for these batteries remains a challenge. Using plant-based compounds as precursors for these redoxmers can decrease their costs and environmental toxicity. In this computational study, flavonoid molecules have been examined as potential redoxmers for O-NRFBs. Flavone and isoflavone derivatives were selected as catholyte (positive charge carrier) and anolyte (negative charge carrier) molecules, respectively. To drive their redox potentials to the opposite extremes, in silico derivatization was performed using a novel algorithm to generate a library of > 40000 candidate molecules that penalizes overly complex structures. A multiobjective Bayesian optimization based active learning algorithm was then used to identify best redoxmer candidates in these search spaces. Our study provides methodologies for molecular design and optimization of natural scaffolds and highlights the need of incorporating expert chemistry awareness of the natural products and the basic rules of synthetic chemistry in machine learning.


Effects of meal-time feeding and protein restriction on walking ability and some bone and carcass properties in broilers.
This experiment was designed to investigate the effects of meal-time feeding and protein restriction on performance, gait score (GS) and carcass and bone traits in broilers. A total of 420 1-day-old chicks were wing banded and randomly distributed into 21 pens with 20 chicks each. At 7 days of age, chicks were weighed and randomly assigned to one of the three treatments: (1) control (C) feed (23.02% crude protein (CP)) was available ad libitum; (2) meal-time feeding (MF); control feed was available from 0100 to 0900 h and from 1500 to 2300 h. Food was withdrawn from 0900 to 1500 h and whole wheat (10 g/bird per day) was dispersed on the floor from 7 to 21 days; and (3) low-protein (LP) diet (19.71% CP) was fed to the chicks from 7 to 21 days. All of the groups were fed ad libitum from 1 to 7 days of age and from 21 to 45 days of age with a standard commercial diet. Individual body weight was measured on days 7, 21 and 45. Feed consumption was measured from 7 to 21 days and from 21 to 45 days. Forty-two chicks were humanly slaughtered and eviscerated for bone evaluation, on days 21 and 45. Also carcass characteristics were determined on day 45. Control group body weight was significantly higher (P < 0.05) at 21 and 45 days of age than the MF and LP groups, which did not differ. Feed intake was reduced by meal-time feeding and LP diet (P < 0.01). Feed efficiency was the best in the MF group during the period of 21 to 45 days of age (P < 0.01). In the control group, shank was significantly longer than that of the LP group and tibia breaking strength was higher than that of the MF group at 21 days (P < 0.05). However, shank width, tibia wet weight and tibia mid-diaphysis ash percentage of the MF group were significantly lower than those of the C and LP groups at 21 days of age (P < 0.05). GS, shank and carcass and tibia bone traits on day 45 were not significant among groups. No compensatory growth and walking ability improvement were observed at 45 days of age for broilers fed with MF and LP between 7 and 21 days of age.


A Comparative ex-vivo Study of Effects of Different Irrigation Protocols with/without Laser Activation on the Root Dentine's Micro-Hardness.
To compare the effects of different irrigation protocols, with/without laser activation, on the radicular dentine's micro-hardness. Eighty-two human extracted premolars were decoronated and divided into 7 groups. Roots were longitudinally split into two halves. The micro-hardness was measured for one half before and after irrigation protocols. The groups were; G1: MTAD without laser-activation, G2: MTAD with laser-activation, G3: sodium-hypochlorite (SH) with laser-activation, G4: SH then EDTA with laser-activation, G5: SH then MTAD with laser-activation, G6: SH without laser-activation. G7: distilled water (control). In the two-irrigants groups G4 and G5), samples were irrigated first with SH then with MTAD or EDTA irrigants, which were activated by the laser. The difference between the before- and after-irrigation micro-hardness was calculated to obtain the micro-hardness difference. Data were analyzed using the Paired Sample-t and Two-ways ANOVA tests at P=0.05. Overall, the mean dentine's micro-hardness after-irrigation (103.1) was lower than before-irrigation (116.1) (P<0.001); except for the distilled-water group, (116.6 and 112.9, respectively) (P=0.075). The micro-hardness reduction of SH without laser-activation group (32.5) was the greatest (P<0.001). The single-irrigant or laser-activation irrigation protocols caused significantly less micro-hardness reduction compared to the two-irrigants or no laser-activation protocols. The mean micro-hardness reduction of SH and MTAD groups (both with laser-activation) (5.8 and 9.3, respectively) were significantly lower than other groups, but not from that of the control group (3.7). Using irrigants significantly reduced the root-dentine's micro-hardness. Although irrigants agitation by an Er: Yag laser significantly minimized micro-hardness reduction, it did not suppress the adverse effects on dentine micro-hardness when two-irrigants were used.


Spatial acoustic radiation of respiratory sounds for sleep evaluation.
Body posture has an effect on sleeping quality and breathing disorders and therefore it is important to be recognized for the completion of the sleep evaluation process. Since humans have a directional acoustic radiation pattern, it is hypothesized that microphone arrays can be used to recognize different body postures, which is highly practical for sleep evaluation applications that already measure respiratory sounds using distant microphones. Furthermore, body posture may have an effect on distant microphone measurement; hence, the measurement can be compensated if the body posture is correctly recognized. A spherical harmonics decomposition approach to the spatial acoustic radiation is presented, assuming an array of eight microphones in a medium-sized audiology booth. The spatial sampling and reconstruction of the radiation pattern is discussed, and a final setup for the microphone array is recommended. A case study is shown using recorded segments of snoring and breathing sounds of three human subjects in three body postures in a silent but not anechoic audiology booth.


Isolation of recombinant field strains of Marek's disease virus integrated with reticuloendotheliosis virus genome fragments.
Two Marek's disease virus (MDV) field strains were isolated from chickens with tumors independently from Guangdong and Guangxi provinces, and it was confirmed that there were no co-infections with reticuloendotheliosis viruses (REV) in chicken embryo fibroblast cells (CEF) in indirect fluorescence antibody test (IFA) with REV-specific monoclonal antibodies. By dot blot hybridization and PCR of genomic DNA of MDV-infected CEF, it was indicated that LTR fragments of REV genome were integrated into genome of these two MDV field strains. To amplify and clone the integrated REV LTR with MDV sequence at the junction, 4 primers from REV LTR and 7 primers from MDV genome fragment with REV LTR insertion hot points were synthesized and 28 (4x7) pairs of primers (one from REV and another from MDV for each pair) were used in PCR while using the genomic DNA of both strains as the templates. The sequence data demonstrated that both recombinant field strains contained the same REV LTR inserted into MDV at the identical sites in US fragment of the genomes. From the above, it was speculated that both recombinant field MDVs were originated from a same recombinant virus and spread among chicken flocks in two provinces.


Associations of plasma C-peptide and IGFBP-1 levels with risk of colorectal adenoma in a multiethnic population.
Circulating levels of insulin and insulin-like growth factor (IGF) hormones have been associated with colorectal cancer risk, but few studies have examined their associations with colorectal adenoma. We measured plasma C-peptide, a marker of insulin secretion, and IGF hormones in a case-control study of 554 pathologically confirmed, first-time adenoma cases and 786 controls with normal endoscopy among Caucasians, Japanese, and Native Hawaiians in Hawaii. High plasma levels of C-peptide were statistically significantly associated with risk of colorectal adenoma [multivariate odds ratio (95% confidence interval) for increasing quartiles: 1.0, 0.91 (0.65-1.27), 1.21 (0.86-1.71), and 1.79 (1.23-2.60); P(trend) = 0.0002]. We also observed a statistically significant inverse association between levels of plasma IGF binding protein-1 (IGFBP-1) and adenoma risk [1.0, 0.97 (0.70-1.34), 0.82 (0.58-1.15), and 0.47 (0.32-0.70); P(trend) <0.0001]. These associations remain significant after adjusting for each other and were not confounded by known risk factors. IGF-I, IGFBP-3, body mass index, and waist or hip circumference were not independently associated with adenoma risk. These results provide evidence for an association of insulin and IGFBP-1 levels with colorectal adenoma. This study suggests that hyperinsulinemia and IGF hormones may act as etiologic factors in colorectal carcinogenesis, as early as during adenoma formation.


Association between maternal gluten intake and type 1 diabetes in offspring: national prospective cohort study in Denmark.
To examine the association between prenatal gluten exposure and offspring risk of type 1 diabetes in humans. National prospective cohort study. National health information registries in Denmark. Pregnant Danish women enrolled into the Danish National Birth Cohort, between January 1996 and October 2002, MAIN OUTCOME MEASURES: Maternal gluten intake, based on maternal consumption of gluten containing foods, was reported in a 360 item food frequency questionnaire at week 25 of pregnancy. Information on type 1 diabetes occurrence in the participants' children, from 1 January 1996 to 31 May 2016, were obtained through registry linkage to the Danish Registry of Childhood and Adolescent Diabetes. The study comprised 101 042 pregnancies in 91 745 women, of whom 70 188 filled out the food frequency questionnaire. After correcting for multiple pregnancies, pregnancies ending in abortions, stillbirths, lack of information regarding the pregnancy, and pregnancies with implausibly high or low energy intake, 67 565 pregnancies (63 529 women) were included. The average gluten intake was 13.0 g/day, ranging from less than 7 g/day to more than 20 g/day. The incidence of type 1 diabetes among children in the cohort was 0.37% (n=247) with a mean follow-up period of 15.6 years (standard deviation 1.4). Risk of type 1 diabetes in offspring increased proportionally with maternal gluten intake during pregnancy (adjusted hazard ratio 1.31 (95% confidence interval 1.001 to 1.72) per 10 g/day increase of gluten). Women with the highest gluten intake versus those with the lowest gluten intake (≥20 v <7 g/day) had double the risk of type 1 diabetes development in their offspring (adjusted hazard ratio 2.00 (95% confidence interval 1.02 to 4.00)). High gluten intake by mothers during pregnancy could increase the risk of their children developing type 1 diabetes. However, confirmation of these findings are warranted, preferably in an intervention setting.


Do different decision-analytic modeling approaches produce different results? A systematic review of cross-validation studies.
When choosing a modeling approach for health economic evaluation, certain criteria are often considered (e.g., population resolution, interactivity, time advancement mechanism, resource constraints). However, whether these criteria and their associated modeling approach impacts results remain poorly understood. A systematic review was conducted to identify cross-validation studies (i.e., modeling a problem using different approaches with the same body of evidence) to offer insight on this topic. With respect to population resolution, reviewed studies suggested that both aggregate- and individual-level models will generate comparable results, although a practical trade-off exists between validity and feasibility. In terms of interactivity, infectious-disease models consistently showed that, depending on the assumptions regarding probability of disease exposure, dynamic and static models may produce dissimilar results with opposing policy recommendations. Empirical evidence on the remaining criteria is limited. Greater discussion will therefore be necessary to promote a deeper understanding of the benefits and limits to each modeling approach.


Large Genomic Rearrangements of Desmosomal Genes in Italian Arrhythmogenic Cardiomyopathy Patients.
Arrhythmogenic cardiomyopathy (AC) is an inherited heart muscle disease associated with point mutations in genes encoding for cardiac desmosome proteins. Conventional mutation screening is positive in ≈50% of probands. Copy number variations (CNVs) have recently been linked to AC pointing to the need to determine the prevalence of CNVs in desmosomal genes and to evaluate disease penetrance by cosegregation analysis in family members. A total of 160 AC genotype-negative probands for 5 AC desmosomal genes by conventional mutation screening underwent multiplex ligation-dependent probe amplification. Nine heterozygous CNVs were identified in 11 (6.9%) of the 160 probands. Five carried a deletion of the entire plakophilin-2 (PKP2) gene, 2 a deletion of only PKP2 exon 4, 1 a deletion of the PKP2 exons 6 to 11, 1 a PKP2 duplication of 5' untranslated region till exon 1, 1 the desmocollin-2 (DSC2) duplication of exons 7 to 9, and 1 a large deletion of chromosome 18 comprising both DSC2 and desmoglein-2 genes. All probands were affected by moderate-severe forms of the disease, whereas 10 (32%) of the 31 family members carrying one of these deletions fulfilled the diagnostic criteria. Genomic rearrangements were detected in ≈7% of AC probands negative for pathogenic point mutations in desmosomal genes, highlighting the potential of CNVs analysis to substantially increase the diagnostic yield of genetic testing. Genotype-phenotype correlation demonstrated the presence of the disease in about one third of family members carrying the CNV, underlying the role of other factors in the development and progression of the disease.


Biomolecular characterization of Antheraea mylitta cocoonase: A secreted protease.
Cocoonase is a protease secreted during the emergence of silk moths. In the present study cocoonase of Antheraea mylitta was collected, purified and secondary structure was determined using circular dichroism (CD) spectroscopy which revealed the presence of α-helix 4.3%, β-sheet 55%, turn 8% and random coil 32.7%. The thermal stability of cocoonase was studied using CD spectroscopy while the thermal property was observed using Differential Scanning Calorimetry (DSC). Furthermore, MALDI-TOF peptide mass fingerprinting (PMF) was performed for similar protein identification using the MASCOT server. Using casein as the substrate, the kinetic constants Km and Vmax were 13 × 103 mg/ml and 15.09 × 10-2 μg/mg.s1 respectively. The specific activity of cocoonase was observed to be maximum at temperature 40 °C, pH-8.0. The effect of heavy metals Hg2+, Cd2+, Co2+, Pb2+ showed inhibitory activity at higher concentrations, while few metals like Mn2+, Fe3+ enhanced the activity while the effect of Ca2+ was not much on the activity. Soybean trypsin inhibitor and PMSF showed an inhibitory effect on the activity of cocoonase. Additionally, antioxidant scavenging and fibrinolytic properties were also observed. Furthermore, the imperative information generated through the present study will serve to explore cocoonase for its prospective pharmaceutical applications.


[Steroid transformation using immobilized microorganisms. II. Degradation of the sidechain of cholesterol by immobilized cells of Nocardia erythropolis].
The degradation of cholesterol side chain was studied by immobilized cells of Nocardia erythropolis in the presence of an inhibitor of the microbial steroid-skeleton-degradation. Different immobilized preparations such as DEAE-cellulose adsorbates, ionic cross-linked polymer gels, i.e., Al/Coalginates and polyacrylates, respectively, and polyethylene maleic acid anhydride supports have shown a high transformation activity yielding the C22- and C19-degradation products. No side chain degradation activity could be observed after immobilization of the cells in polyacrylamide gel under usual conditions caused by the toxic effect of the acrylamide monomer on the Nocardia cells.


The cost of public health interventions to respond to the 10th Ebola outbreak in the Democratic Republic of the Congo.
The 10th Ebola virus disease (EVD) outbreak in the Democratic Republic of the Congo (DRC) drew substantial attention from the international community, which in turn invested more than US$1 billion in EVD control over two years (2018-2020). This is the first EVD outbreak to take place in a conflict area, which led to a shift in strategy from a pure public health response (PHR) to a multisectoral humanitarian response. A wide range of disease control and mitigation activities were implemented and were outlined in the five budgeted Strategic Response Plans used throughout the 26 months. This study used the budget/expenditure and output indicators for disease control and mitigation interventions compiled by the government of DRC and development and humanitarian partners to estimate unit costs of key Ebola control interventions. Of all the investment in EVD control, 68% was spent on PHR. The remaining 32% covered security, community support interventions for the PHR. The disbursement for the public health pillar was distributed as follows: (1) coordination (18.8%), (2), clinical management of EVD cases (18.4%), (3) surveillance and vaccination (15.9%), (4) infection prevention and control/WASH (13.8%) and (5) risk communication (13.7%). The unit costs of key EVD control interventions were as follows: US$66 182 for maintaining a rapid response team per month, US$4435 for contact tracing and surveillance per identified EVD case, US$1464 for EVD treatment per case, US$59.4 per EVD laboratory test, US$120.7 per vaccinated individual against EVD and US$175.0 for mental health and psychosocial support per beneficiary. The estimated unit costs of key EVD disease control interventions provide crucial information for future infectious disease control planning and budgeting, as well as prioritisation of disease control interventions.


The Link Between Structural and Functional Brain Abnormalities in Depression: A Systematic Review of Multimodal Neuroimaging Studies.
Adequate and timely identification of depression is essential to improve patient care. A potential method to achieve this is by using neuroimaging. Many neuroimaging studies have revealed widespread abnormalities in brain structure and function in patients with depression, but in most studies only single neuroimaging modalities were used. Links between abnormalities in brain structure and function need to be therefore further explored in order to define diagnostic and therapeutic applications. A systematic literature review according to preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines was conducted. Out of 2,516 articles, only 14 studies were eligible to be included. These studies combined structural and functional neuroimaging methods in depressed patients compared to controls. Four studies reported a negative relationship between brain structure and function within the default mode network: reduced gray or white matter integrity in depressed patients compared to healthy controls was associated with enhanced neural activity or connectivity. The other studies reported positive relationships (two studies), mixed relationships (two studies), or no link (six studies) between structural and functional brain abnormalities. This systematic literature review revealed no robust relationship between abnormalities in brain structure and function in patients with depression. Remarkably, only 14 studies could be included and four of these suggested enhanced default mode network connectivity associated with reduced structural brain integrity. In the ongoing development of the diagnostic and treatment applications of neuroimaging, large-scale studies that combine structural with functional neuroimaging are required to determine the relationship between structural and functional abnormalities in depression.


How well do the theory of reasoned action and theory of planned behaviour predict intentions and attendance at screening programmes? A meta-analysis.
Meta-analysis was used to quantify how well the Theories of Reasoned Action and Planned Behaviour have predicted intentions to attend screening programmes and actual attendance behaviour. Systematic literature searches identified 33 studies that were included in the review. Across the studies as a whole, attitudes had a large-sized relationship with intention, while subjective norms and perceived behavioural control (PBC) possessed medium-sized relationships with intention. Intention had a medium-sized relationship with attendance, whereas the PBC-attendance relationship was small sized. Due to heterogeneity in results between studies, moderator analyses were conducted. The moderator variables were (a) type of screening test, (b) location of recruitment, (c) screening cost and (d) invitation to screen. All moderators affected theory of planned behaviour relationships. Suggestions for future research emerging from these results include targeting attitudes to promote intention to screen, a greater use of implementation intentions in screening information and examining the credibility of different screening providers.